Current therapy for Parkinson's disease is limited to the alleviation of the symptoms, but no agent has yet been identified capable of counteracting the establishment and the progress of the degeneration of the dopaminergic neurons of the substantia nigra linked with deficient dopamine levels of the basal ganglia in turn responsible for the appearance of the complex symptomatology of this pathology. This is characterised by rigidity, tremors, bradykinesia, akinesia, posture changes; manifestations that represent a serious threat to the health of the individual with Parkinson's disease.
Among the therapeutic strategies currently used to improve the quality of life of these subjects, are therapeutic approaches which aim to replenish the missing neurotransmitter. One example is represented by the use of L-DOPA, in combination with carbidopa or benserazide (inhibitors of the peripheral amino acid decarboxylases enzymes). This therapy is one of the most effective and currently used against the appearance of changes in motor function which are manifested when the physiology of the dopaminergic system is severely compromised.
However, in the long run, this therapeutic approach is subject to a lowering of efficacy. Indeed, patients subjected to chronic treatment with L-DOPA frequently display an emphasising of said manifestations, in addition to the appearance of other side effects, due to the inherently neurotoxic properties possessed by L-DOPA.
Alternatively, the use of dopaminergic receptor agonists has been introduced, however they do not display the same efficacy as L-DOPA; or of monoamine oxidase inhibitors and of the muscarinic acetyl choline receptor antagonists. The use of the latter brings about the appearance of serious side effects and cognitive impairment, as a consequence of the receptor interactions these products establish, both at the systemic level and at the central nervous system level.
In recent years, with the discovery of the role of adenosine as a neurotransmitter, its receptors and their functional characterisation, the hypothesis of using antagonists of the adenosine A2a receptor as therapeutic agents for the treatment of the motor disorders associated with Parkinson's disease has gained credit. (P. J. Richardson, H. Kase and P. G. Jenner Trends Pharm. Sci 1997, 18:338-345).
Recent experimental evidence has allowed the understanding of the distribution, the function and the physiology of this receptor at the level of the central nervous system, permitting the conclusion that blocking the A2a receptor can modulate cholinergic, gabaergic and glutamatergic neurotransmission, in order to establish, at the level of the basal ganglia output neurons, a neurochemical order which can adequately compensate acute or chronic Dopamine deficiency in the nigrostriatal system.
Furthermore, it has been observed that the A2a receptor is functionally associated with that for Dopamine D2 and that the stimulation of the former can reduce the binding capacity of the latter for Dopamine. Thus it follows, that the blocking of the A2a adenosine receptor increases the interactive capacity of D2 receptors towards Dopamine, favouring binding even in the presence of low levels of this neurotransmitter in the synaptic space. (Ferre S., e al. (1991) Proc. Nat. Acc. Sci. U.S.A. 88, 7237-7241). For these reasons, selective antagonists of the A2a receptor have been proposed as agents for the treatment of motor disorders, with particular regard to Parkinson's disease.
In addition, it has been demonstrated that these agents offer an effect that is synergic to the treatment with L-DOPA or with dopamine agonists, and can be used in conjunction with the Dopamine-substitutive therapies. In this case, the use of receptor A2a selective antagonists represents a further therapeutic advantage since, the dosages normally required for L-DOPA therapeutic treatment could be reduced in quantity, or frequency of administration, thereby conserving the therapeutic efficacy.
The present invention relates. to compounds with affinity for the adenosine A2a receptor, active as antagonists, useful in the preparation of medicaments for the treatment of motor disorders in individuals, which are associated with functional alterations in the basal ganglia, forming part of the symptomatology of diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease and Wilson's disease; brought about by drugs (parkinsonism of classic neuroleptics) trauma, toxic agents (NOTP, manganese, carbon monoxide).
The present invention can also be used in the treatment of Parkinson's disease with “on-off” phenomena and Parkinson's disease with preponderant dyskinesia.
In addition, having been demonstrated that, following ischaemic damage to the central nervous system, adenosine A2a receptor antagonists can inhibit the toxic effects induced by the excitatory amino acids released in abundance after such phenomena, cerebral ischaemia and the mechanisms associated with neurodegenerative processes represent other “targets” towards which A2a receptor antagonists can display their therapeutic actions.
Selective antagonists of the adenosine A2a receptor are described in CA 1.242.368, Boehringer Ingelheim, in the form of imidazo-triazole-pyrimidine derivatives, in which their activity towards the A1 receptor prevails towards the A2 receptor; in WO 01/02409, Vernalis Res Ltd, derivatives of thieno- and furopyrimidine are described as compounds useful in the treatment of motor disorders, for example Parkinson; WO 00/24742, Fusijawa Pharm Co Ltd, describes derivatives of pyrazolopyridine with dual antagonistic action against the A1 and A2 receptors; WO 00/17201 and WO 98/42711, Kyowa Hakko K K K, describe derivatives of 1,2,4-triazolo-(1,5-c)pyrimidine; WO 00/13682, WO 00/13681 and WO 99/26627, Cerebrus Pharm Ltd, describe derivatives of 4-quinolinemethanol; WO 99/62518, Cadus Pharm Corp, describe 7-deazapurine N-6 substitutions with activity profiles as A1, A2, A2a, A2b, A3 receptor antagonists; WO 99/43678, Kyowa Hakko K K K, describe derivatives of 1,2,4-triazolo-(1,5-a)-pyrimidine; WO 95/01356 and WO 98/52568, Schering Plough SpA, describe 1,2,4-triazolo-(1,5-c)-pyrimidine.
Amongst the A2a receptor antagonists in advanced testing phase, we can mention compounds KW-6002 and KW-1783, described in EP 0 628 311, which can be characterised as xanthine derivatives. These products possess a (3,4-dimethoxyphenyl)ethylenic group in position 8, and are subject to loss of activity through photoisomerisation of the ethylenic bond (Annals New York Academy of Sciences—Ongini E.; Adami M; Ferri C; and Bertorelli R.; Trends in Pharm. Sci. 1996 Vol. 17 364-72). The compound KW 6002 is currently undergoing clinical trials (phase II as an antidepressant and phase III as an antiparkinson agent; Pharmaprojects Acc. No. 23891). Another selective antagonist of the A2a receptor is the product SCH 63390 (Pharmaproject Acc. No29842), in pre-clinical trials. ZM 241385 from Astra Zeneca (EP 0 459 702) is a potent selective antagonist; for this reason, utilised for pharmacological investigations (Ji X. D., Jacobson K. A., Drug Des. Discov. 1999, 16:217-226; Pharmaproject Acc. No 22730). Despite its high selectivity and affinity, in vivo the product has shown very low bioavailability (El Yacoubi M; et al Eur. J. Pharm. 401 (2000) 63-77).